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Assay Development for High Content Quantification of Sod1 Mutant Protein Aggregate Formation in Living Cells
Published on: October 4, 2017
Small peptides against the mutant SOD1/Bcl-2 toxic mitochondrial complex restore mitochondrial function and cell
Wenzhi Tan1, Nicole Naniche, Alexey Bogush
1Frances and Joseph Weinberg Unit for ALS Research, Farber Institute for Neurosciences, Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Abstract:
Mutations in superoxide dismutase 1 (SOD1) cause amyotrophic lateral sclerosis (ALS) in 20% of familial cases (fALS). Mitochondria are one of the targets of mutant SOD1 (mutSOD1) toxicity. We previously demonstrated that at the mitochondria, mutSOD1 forms a toxic complex with Bcl-2, which is then converted into a toxic protein via a structural rearrangement that exposes its toxic BH3 domain (Pedrini et al., 2010). Here we now show that formation of this toxic complex with Bcl-2 is the primary event in mutSOD1-induced mitochondrial dysfunction, inhibiting mitochondrial permeability to ADP and inducing mitochondrial hyperpolarization. In mutSOD1-G93A cells and mice, the newly exposed BH3 domain in Bcl-2 alters the normal interaction between Bcl-2 and VDAC1 thus reducing permeability of the outer mitochondrial membrane. In motor neuronal cells, the mutSOD1/Bcl-2 complex causes mitochondrial hyperpolarization leading to cell loss. Small SOD1-like therapeutic peptides that specifically block formation of the mutSOD1/Bcl-2 complex, recover both aspects of mitochondrial dysfunction: they prevent mitochondrial hyperpolarization and cell loss as well as restore ADP permeability in mitochondria of symptomatic mutSOD1-G93A mice.
Insights
Mutant superoxide dismutase 1 (SOD1) triggers toxic protein formation in mitochondria, causing amyotrophic lateral sclerosis (ALS). Therapeutic peptides targeting this complex restore mitochondrial function and prevent cell loss in ALS models.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Mutations in superoxide dismutase 1 (SOD1) are a significant cause of familial amyotrophic lateral sclerosis (fALS).
- Mitochondria are key targets of mutant SOD1 (mutSOD1) toxicity.
- Previous work identified a toxic mutSOD1/Bcl-2 complex in mitochondria.
Purpose of the Study:
- To investigate the primary role of the mutSOD1/Bcl-2 complex in mitochondrial dysfunction in ALS.
- To elucidate the downstream effects of this complex on mitochondrial permeability and membrane potential.
- To evaluate the therapeutic potential of blocking this complex.
Main Methods:
- Cellular and animal models of SOD1-G93A mutant-induced ALS.
- Analysis of mitochondrial ADP permeability and membrane potential (hyperpolarization).
- Assessment of motor neuron cell loss.
- Testing of small SOD1-like therapeutic peptides.
Main Results:
- Formation of the mutSOD1/Bcl-2 complex is the primary cause of mitochondrial dysfunction in ALS.
- This complex inhibits ADP permeability and induces mitochondrial hyperpolarization.
- The exposed BH3 domain in Bcl-2 disrupts Bcl-2/VDAC1 interaction, reducing outer mitochondrial membrane permeability.
- Therapeutic peptides blocking the mutSOD1/Bcl-2 complex restored mitochondrial function and prevented cell death in ALS models.
Conclusions:
- The mutSOD1/Bcl-2 complex is a critical initiator of mitochondrial pathology in SOD1-ALS.
- Targeting this complex with specific peptides offers a promising therapeutic strategy for ALS.
- Restoration of mitochondrial function is achievable through intervention at the mutSOD1/Bcl-2 complex level.
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